Mechanisms of Acquired Drug Resistance to the HDAC6 Selective Inhibitor Ricolinostat Reveals Rational Drug-Drug Combination with Ibrutinib.

TitleMechanisms of Acquired Drug Resistance to the HDAC6 Selective Inhibitor Ricolinostat Reveals Rational Drug-Drug Combination with Ibrutinib.
Publication TypeJournal Article
Year of Publication2017
AuthorsAmengual JE, Prabhu SA, Lombardo M, Zullo K, Johannet PM, Gonzalez Y, Scotto L, Serrano XJirau, Wei Y, Duong J, Nandakumar R, Cremers S, Verma A, Elemento O, O'Connor OA
JournalClin Cancer Res
Date Published2017 Jun 15
KeywordsAnimals, Antineoplastic Combined Chemotherapy Protocols, Apoptosis, Cell Line, Tumor, Drug Resistance, Neoplasm, Drug Synergism, Histone Deacetylase 6, Histone Deacetylase Inhibitors, Humans, Hydroxamic Acids, Lymphoma, Mice, Pyrazoles, Pyrimidines, Xenograft Model Antitumor Assays

Pan-class I/II histone deacetylase (HDAC) inhibitors are effective treatments for select lymphomas. Isoform-selective HDAC inhibitors are emerging as potentially more targeted agents. ACY-1215 (ricolinostat) is a first-in-class selective HDAC6 inhibitor. To better understand the discrete function of HDAC6 and its role in lymphoma, we developed a lymphoma cell line resistant to ACY-1215. The diffuse large B-cell lymphoma cell line OCI-Ly10 was exposed to increasing concentrations of ACY-1215 over an extended period of time, leading to the development of a resistant cell line. Gene expression profiling (GEP) was performed to investigate differentially expressed genes. Combination studies of ACY-1215 and ibrutinib were performed in cell lines, primary human lymphoma tissue, and a xenograft mouse model. Systematic incremental increases in drug exposure led to the development of distinct resistant cell lines with IC values 10- to 20-fold greater than that for parental lines. GEP revealed upregulation of MAPK10, HELIOS, HDAC9, and FYN, as well as downregulation of SH3BP5 and LCK. Gene-set enrichment analysis (GSEA) revealed modulation of the BTK pathway. Ibrutinib was found to be synergistic with ACY-1215 in cell lines as well as in 3 primary patient samples of lymphoma. confirmation of antitumor synergy was demonstrated with a xenograft of DLBCL. The development of this ACY-1215-resistant cell line has provided valuable insights into the mechanistic role of HDAC6 in lymphoma and offered a novel method to identify rational synergistic drug combinations. Translation of these findings to the clinic is underway. .

Alternate JournalClin. Cancer Res.
PubMed ID27993968
PubMed Central IDPMC5474138
Grant ListR01 CA194547 / CA / NCI NIH HHS / United States
U24 CA210989 / CA / NCI NIH HHS / United States
UL1 TR000004 / TR / NCATS NIH HHS / United States